Phosphorus plays an important role in normal human physiology. It is a constituent of nucleic acids, phospholipids, high energy intermediates, and hydroxyapatite which in turn is the major component of bone mineral. Phosphorus is absorbed by and secreted into the intestine, and inorganic phosphates are filtered by the renal glomerulus and reabsorbed by the proximal tubule of the kidney. Thus, the intestine and kidney play key roles in controlling phosphorus homeostasis.
Several factors alter the efficiency with which the intestine and kidney absorb or reabsorb phosphorus. Important among these are the amount of phosphorus ingested in the diet and the rate of sodium reabsorption in the proximal tubule. Hormones such as 1,25-dihydroxyvitamin D.sub.3, parathyroid hormone (PTH), growth hormone, insulin-like growth factor and insulin alter the efficiency of phosphate retention in the organism by acting on intestinal or renal epithelia. The effects of 1,25-dihydroxyvitamin D.sub.3, and parathyroid hormone, however, are primarily on calcium absorption whereas the effects of growth hormone, insulin-like growth factor and insulin are primarily on anabolic phenomena, cell growth and glucose metabolism. Clearly, the ability of the organism to control phosphorus balance independent of calcium balance would be of biological and homeostatic advantage. A factor (or factors) that specifically alters phosphorus metabolism independent of changes in other metabolic pathways has not been characterized.
Cai et al. (New Eng. J. Med., 330, 1645 (1994)) described the presence of a heat labile, 8,000-25,000 dalton, inhibitor of renal epithelial cell sodium-dependent phosphate transport in supernatants of cultured sclerosing hemangioma cells. These cells were derived from a tumor of a patient with oncogenic osteomalacia and hypophosphatemia. The patient's hypophosphatemia and urinary phosphate wasting were cured upon removal of the tumor. The factor(s) specifically inhibited renal epithelial phosphate transport but not glucose or alanine transport. Supernatants from these tumor cells also contained a substance that cross-reacted with PTH-like antisera but not PTH-related antisera. The mechanism of action of the factor(s) was distinct from that of PTH because the factor(s) inhibited phosphate transport in renal epithelial cells without increasing cAMP concentrations and its action was not blocked by a PTH antagonist. parathyroid hormone antibodies. However, the factor was not further characterized.
Thus, them is a need to identify and isolate genes that encode factors that alter phosphate uptake in the kidney.